Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.

Children with autistic spectrum disorders (ASDs) tend to suffer from severe gastrointestinal problems. Such symptoms may be due to a disruption of the indigenous gut flora promoting the overgrowth of potentially pathogenic micro-organisms. The faecal flora of patients with ASDs was studied and compared with those of two control groups (healthy siblings and unrelated healthy children). Faecal bacterial populations were assessed through the use of a culture-independent technique, fluorescence in situ hybridization, using oligonucleotide probes targeting predominant components of the gut flora. The faecal flora of ASD patients contained a higher incidence of the Clostridium histolyticum group (Clostridium clusters I and II) of bacteria than that of healthy children. However, the non-autistic sibling group had an intermediate level of the C. histolyticum group, which was not significantly different from either of the other subject groups. Members of the C. histolyticum group are recognized toxin-producers and may contribute towards gut dysfunction, with their metabolic products also exerting systemic effects. Strategies to reduce clostridial population levels harboured by ASD patients or to improve their gut microflora profile through dietary modulation may help to alleviate gut disorders common in such patients.

The role of regulated clinical trials in the development of bacteriophage therapeutics.

Antibiotic resistance is now recognized as a major, global threat to human health and the need for the development of novel antibacterial therapies has become urgent. Lytic bacteriophages (phages) targeting individual bacterial pathogens have therapeutic potential as an alternative or adjunct to antibiotic use. Bacteriophage therapy has been used for decades, but clinical trials in this field are rare, leaving many questions unanswered as to its effectiveness for many infectious diseases. As a consequence bacteriophage therapy is not used or accepted in most parts of the world. The increasing need for new antimicrobial therapies is driving the development of bacteriophage therapies for a number of diseases but these require the successful completion of large-scale clinical trials in accordance with US FDA or European EMA guidelines. Bacteriophages are considered as biological agents by regulatory authorities and they are managed by biological medicinal products guidelines for European trials and guidelines of the division of vaccines and related product applications in the USA. Bacteriophage therapy is typically an 'active' treatment requiring multiplication in the bacterial host and therefore the factors that govern its success are different from those of conventional antibiotics. From the pharmacokinetic and pharmacodynamic points of view, time of treatment, dosage depending on the site of infection and the composition of the bacteriophage formulation (single vs multiple strains) need careful consideration when designing clinical trials. Scientific evidence regarding inflammatory effects, potential for gene transfer and phage resistance, need to be evaluated through such trials. However purity, stability and sterility of preparations for human use can be addressed through Good Manufacturing Practises to reduce many potential safety concerns. In this review we discuss the potential for the development of bacteriophage therapy in the context of critical aspects of modern, regulated clinical trials.